References
The following references are referred to by numbers in parentheses at the relevant portion of the specification.    1. Gupta and Robinson, Treatise on Oral Controlled-drug Delivery, Text Ed. 1992, edited by Aegis Cadence, Mandel Decker, Inc.    2. Traber et al., Helv. Chim. Acta, 60: 1247-1255 (1977)    3. Kobel et al., Europ. J. Applied Microbiology and Biotechnology, 14: 237-240 (1982)    4. von Wartburg et al., Progress in Allergy, 38: 28-45 (1986)    5. Rich et al. (J. Med. Chem., 29: 978 (1986)    6. U.S. Pat. No. 4,384,996, issued on May 24, (1983)    7. U.S. Pat. No. 4,771,122, issued on Sep. 13, (1988)    8. U.S. Pat. No. 5,284,826, issued on Feb. 8, (1994)    9. U.S. Pat. No. 5,525,590, issued on Jun. 11, (1996)    10. Sketris et al., Clin. Biochem., 28: 195-211 (1995)    11. Bennett, Renal Failure, 20: 687-90 (1998)    12. Wang et al., Transplantation, 58:940-946 (1994)    13. “Eastman Vitamin E TPGS”, Eastman Brochure, Eastman Chemical Co., Kingsport, Tenn. (October 1996)    14. Hawley's Condensed Chemical Dictionary, (1987)    15. Ellis, Progress in Medicinal Chemistry 25, (1988) Elsevier, Amsterdam    16. Sokol, R. J., Lancet, 338(8761): 212, (1991)    17. Sokol, R. J., Lancet, 338(8768): 697, (1991)
The disclosure of each of the above publications or patents is hereby incorporated by reference in its entirety to the same extent as if the language of each individual publication and patent were specifically and individually incorporated by reference.
The Use of Cyclosporin as a Therapeutic Agent
Despite efforts to avoid graft rejection through host-donor tissue type matching, in the majority of transplantation procedures, immunosuppressive therapy is critical to the viability of the donor organ in the host. A variety of immunosuppressive agents have been employed in transplantation procedures, including azathioprine, methotrexate, cyclophosphamide, FK-506, rapamycin and corticosteroids. Cyclosporins are finding increasing use in immunosuppressive therapy due to their preferential effect on T-cell mediated reactions (1).
Cyclosporin is a potent immunosuppressive agent that has been demonstrated to suppress humoral immunity and cell-mediated immune reactions such as allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis and graft versus host disease (GVHD). It is used for the prophylaxis of organ rejection subsequent to organ transplantation, for treatment of rheumatoid arthritis, for the treatment of psoriasis and for the treatment of other autoimmune diseases such as type I diabetes, Crohn's disease and lupus. Many naturally occurring cyclosporins are well known in the art. Non-natural cyclosporins have been prepared by total- or semi-synthetic means or by the application of modified culture techniques. Thus, the class of available cyclosporins is substantial, and includes, for example, the naturally occurring cyclosporins A (CsA) through Z (CsZ), as well as other non-natural cyclosporin derivatives such as dihydro- and iso-cyclosporins (2, 3, 4). CsA analogs containing modified amino acids in the 1-position have been reported by Rich et al. (5). Immunosuppressive, anti-inflammatory and anti-parasitic CsA analogs are described in U.S. Pat. Nos. 4,384,996 (6), 4,771,122 (7), 5,284,826 (8) and 5,525,590 (9), assigned to Sandoz.
Cyclosporin is a lipophilic molecule having a molecular weight of 1202 daltons. Owing to the poor solubility in water and the high lipophilicity of cyclosporin A, pharmaceutical compositions of cyclosporin A with customary solid or liquid pharmaceutical carriers often have disadvantages. For example, the cyclosporins are not satisfactorily absorbed from such compositions, or the compositions are not well tolerated, or they are not sufficiently stable when stored. Often, the dissolved concentration is low in relation to the daily dose.
Adverse Effects of Cyclosporin Therapy
There are numerous adverse effects associated with cyclosporin therapy. These include nephrotoxicity, hepatotoxicity, cataractogenesis, hirsutism, parathesis and gingival hyperplasia (10). The most serious adverse effect is nephrotoxicity.
Acute cyclosporin nephrotoxicity is accompanied morphologically by tubular lesions characterized by inclusion bodies, isometric vacuolation and microcalcification. That leads to a decrease in the glomerular filtration rate, which can be identified by the rapid increase in serum creatinine in patients treated with cyclosporin (11).
The exact mechanism by which cyclosporin causes renal injury is not known. In rat studies, chronic CsA-induced functional and structural deterioration of the kidney was accompanied by renal lipid peroxidation. It has been shown by Wang et al. that co-administration of an anti-oxidant with CsA reduced the renal injury in the rat (12).
Previous attempts in the art to reduce the nephrotoxic risks associated with cyclosporin therapy include the co-administration of the drug with an agent that delays the metabolism of cyclosporin, effectively reducing the dose required to maintain therapeutic blood levels. However, this method often does not resolve the problem of high variation of cyclosporin bioavailability (12). Thus, the problem of preparing a cyclosporin formulation that has excellent bioavailability but which does not cause adverse side effects is well known in the art.
Dosage Forms
In order for a drug to perform its therapeutic activity, a therapeutic amount of the drug must be made bioavailable, i.e., it must be able to get to the site of action in the patient. Oral drug delivery is known in the art, and popular because of ease of administration. However, oral dosage forms are complicated by the fact that the drug must first be released from the dosage form over a given time in the gut, and must be solubilized and absorbed in the gastrointestinal tract. Thus, proper drug release from the dosage form and solubilization of the drug in the gastrointestinal (GI) tract are critical.
Well known oral dosage forms that work well within the confines of the GI tract include tablets, capsules, gel capsules, syrups, suspensions, emulsions, microemulsions and pre-emulsion concentrates. Solubility plays a large role in the development of oral dosage formulations, because the formulation used to deliver the active drug will affect the amount and/or concentration of the drug that reaches the active site over a given period of time. The composition of the formulation also directly affects the solubilization of the drug compound in the gastrointestinal tract, and consequently the extent and rate of the absorption of the active drug compound into the blood stream. In addition, the therapeutic value of a drug is affected by the rate in which the drug is released from the delivery system itself, which in turn affects the rate and extent of solubilization of the active compound in the gastrointestinal tract before absorption (1).
In conventional systems known in the art, drug content is released into the gastrointestinal tract within a short period of time, and plasma drug levels peak at a given time, usually within a few hours after dosing. The design of known oral drug delivery systems, including cyclosporin formulations, is based on obtaining the fastest possible rate of drug dissolution at the risk of creating undesirable, dose related side effects.
Thus, there is a serious need for cyclosporin formulations with reduced toxicity but which retain high levels of bioavailability, and which do not need to be administered with another agent.